RNA editing (ADAR) therapeutics

01Overview and value chain#

Markers EC: FDA orphan-drug designation + accelerated-approval pathway; Directive 2001/83/EC | OECD: Bio-pharma | Regulator: FDA (USA), EMA (European Union), NMPA (China)

RNA editing therapeutics correct disease-causing transcripts at the RNA level rather than in the genome. Engineered oligonucleotides — Wave’s AIMers, Korro’s OPERA guides, ProQR’s Axiomer EONs, HuidaGene’s arRNAs — recruit the cell’s endogenous adenosine deaminase acting on RNA (ADAR) enzymes to convert a pathogenic adenosine to inosine (A-to-I, read as guanosine), repairing mutant mRNA without any permanent change to the DNA. Because the edit is made on the transcript, it is reversible and dose-titratable, with no bystander edits, no indels and no lasting genome alteration — the safety advantages the modality holds over DNA base editing. The field’s lead asset, Wave’s WVE-006 (a GalNAc-conjugated AIMer for alpha-1 antitrypsin deficiency, AATD), generated wild-type M-AAT at 64% of total AAT and cut toxic Z-AAT by 71% in the RestorAATion-2 trial, reaching 11.9 µM total AAT with editing sustained for at least three months after the last dose; ProQR’s AX-0810 then delivered the first clinical validation of an RNA-editing platform with an 8-fold NTCP target-engagement signal, and Korro’s KRRO-111 achieved more than 90% SERPINA1 editing in vivo. Delivery is dominated by subcutaneous GalNAc conjugation that routes the oligo to hepatocytes via ASGPR, avoiding lipid nanoparticles; no RNA-editing drug is approved yet, and FDA feedback on an accelerated-approval pathway for WVE-006 is expected mid-2026.

The key directions of RNA editing therapeutics are:

1. AATD RNA editors (AATD Editor): GalNAc ADAR-recruiting oligonucleotides that repair the SERPINA1 Z-allele transcript, restoring protective M-AAT and clearing toxic Z-AAT in the liver — Wave (WVE-006), Korro (KRRO-110, KRRO-111).
2. Liver and metabolic editors (Metabolic Editor): RNA editing of hepatocyte transporters and metabolic enzymes beyond AATD — ProQR (AX-0810/AX-0811 on NTCP for cholestatic liver disease, AX-2911 on PNPLA3 for MASH).
3. ADAR-recruitment platforms (Editing Platform): the guide-RNA and chemically modified oligonucleotide chemistries that recruit endogenous ADAR1/ADAR2 without delivering any exogenous enzyme — Wave AIMer, Korro OPERA, ProQR Axiomer, HuidaGene LEAPER.
4. CNS and rare-disease editors (CNS Editor): extension of A-to-I editing to neuronal and rare-genetic targets through partnered programs — ProQR (AX-2402 for Rett syndrome MECP2, with the Rett Syndrome Research Trust; Eli Lilly CNS collaboration).

Sectoral value chain#

[pathogenic A-to-I target on mRNA] ──> [ADAR-recruiting oligo (AIMer/EON/arRNA) design + synthesis] ──> [GalNAc-conjugated subcutaneous editor]
                                                       │
                                              (endogenous ADAR A-to-I edit, reversible)
                                                       │
                                                       ▼
[clinical candidate] <─── [editing PD/PK + Phase 1-2 trials] <─────┘

Value chain levels#

Cross-cutting technologies of the sector:

• Endogenous ADAR recruitment (ADAR Recruitment): all four platforms recruit the cell’s own ADAR1/ADAR2 via a guide oligo, avoiding exogenous-protein delivery and so lowering cargo size and immunogenicity versus CRISPR-base-editor proteins.
• GalNAc hepatocyte delivery (GalNAc Delivery): subcutaneous GalNAc conjugation routes the editor to hepatocytes through the asialoglycoprotein receptor, enabling liver-directed A-to-I editing without lipid nanoparticles and supporting infrequent (monthly or longer) dosing.
• Reversible, titratable editing (Reversible Editing): because the edit sits on the transcript and not the genome, RNA editing is transient and dose-adjustable, with no bystander edits or permanent genome change — the central safety differentiator versus DNA editing.

02US#

The US leads RNA-editing therapeutics clinically, with the field’s two most advanced AATD programs — Wave’s WVE-006 in Phase 1b/2a and Korro’s OPERA platform — both run from Cambridge, MA, under an FDA framework built on orphan-drug designation and the accelerated-approval pathway.

Wave, Korro, FDA#

• Wave Life Sciences: WVE-006, a GalNAc-conjugated AIMer for AATD, is the modality’s lead asset; RestorAATion-2 data (May 2026) showed 64% wild-type M-AAT, a 71% reduction in toxic Z-AAT, 11.9 µM total AAT on 200 mg biweekly dosing (13.6 µM on 400 mg monthly), and editing sustained at least three months after the last dose, with no liver toxicities; FDA feedback on an accelerated-approval pathway is expected mid-2026.
• Korro Bio: the OPERA (Oligonucleotide Promoted Editing of RNA) platform underpins KRRO-110 (in the REWRITE Phase 1/2a study, with FDA orphan-drug designation granted in March 2025) and the newly selected development candidate KRRO-111, which achieved more than 90% SERPINA1 transcript editing and roughly 90% repaired functional AAT protein in a PiZZ mouse model; the company held $157.1M in cash and marketable securities at 31 March 2026, with a runway into H2 2028.
• FDA framework: RNA-editing oligonucleotides are reviewed under the FDA’s oligonucleotide-therapeutics pathway, with orphan-drug designation and the accelerated-approval route available for AATD (a rare disease affecting fewer than 200,000 people in the US); WVE-006’s mid-2026 regulatory feedback is the modality’s first such checkpoint.

03CN#

China’s RNA-editing strength is foundational rather than commercial: Wensheng Wei’s group at Peking University and Changping Laboratory originated the LEAPER platform, whose 2026 LEAPER 3.0 iteration is the field’s leading structure-guided guide-RNA design, with HuidaGene as the translation vehicle.

HuidaGene, LEAPER, NMPA#

• HuidaGene: is commercializing the LEAPER (Leveraging Endogenous ADAR for Programmable Editing of RNA) platform from Wei’s PKU lab; LEAPER uses a single engineered ADAR-recruiting RNA (arRNA) to direct endogenous ADAR to a target adenosine, with no exogenous enzyme and therefore low immunogenicity and a small delivery payload.
• LEAPER lineage: LEAPER 1.0 was published in Nature Biotechnology in 2019 (linear arRNA), LEAPER 2.0 in 2022 introduced circular circ-arRNA for higher editing efficiency and lower off-target editing, and LEAPER 3.0 (Cell, 10 June 2026) uses AlphaFold 3 structural prediction to design dual-bulge arRNAs that expand the set of editable sites and eliminate bystander editing.
• NMPA framework: RNA-editing therapeutics are reviewed under the NMPA’s oligonucleotide and biologics framework; the LEAPER platform’s progress rests on National Natural Science Foundation of China funding (grants 82341207 and 31930016) and Beijing municipal science-and-technology support, with clinical translation still ahead of the US leaders.

04EU#

Europe’s role in RNA editing is concentrated in ProQR Therapeutics (Leiden, NL), whose Axiomer platform delivered the first clinical validation of an RNA-editing oligonucleotide and is scaled through a deepening Eli Lilly partnership.

ProQR, Axiomer, EMA#

• ProQR Therapeutics: the Axiomer platform uses ADAR-recruiting editing oligonucleotides (EONs); AX-0810, a GalNAc-conjugated EON modulating NTCP for cholestatic liver disease, produced the first clinical validation of the platform in 2026 — a dose-dependent up to 8-fold rise in total bile acids at 6 mg/kg (above the 2-fold target-engagement threshold) with an estimated half-life of about 8 weeks and no serious adverse events; the follow-on AX-0811 has a clinical-trial application planned mid-2026, and development candidates AX-2402 (Rett syndrome) and AX-2911 (MASH) extend the pipeline.
• Eli Lilly partnership: Lilly has been tied to the Axiomer platform since 2021 (liver and nervous-system targets), expanded in 2022, with ProQR eligible for up to about $3.75bn in milestones plus royalties; Lilly maintained its pro-rata ownership in ProQR’s $59.2M June 2026 raise (buying about $9.2M of shares alongside a $50M public offering at $1.81 per share).
• EMA framework: RNA-editing oligonucleotides will be reviewed as MAA drugs by the European Medicines Agency under Directive 2001/83/EC; ProQR divested its late-stage ophthalmic assets (sepofarsen, ultevursen) in 2023 to focus entirely on Axiomer, and no RNA-editing drug is yet EU-approved.

05Leading companies and research institutes#

06Tech stack and innovations#

The stack pairs ADAR-recruiting oligonucleotide chemistry with GalNAc hepatocyte delivery and structure-guided guide-RNA design, yielding a reversible A-to-I edit on a disease transcript.

1. ADAR-recruiting oligonucleotides (Editing Oligo):
   • Wave’s AIMer (stereopure), Korro’s OPERA, ProQR’s Axiomer EON and HuidaGene’s arRNA are chemically modified oligos that recruit endogenous ADAR1/ADAR2 to a target adenosine; WVE-006 generated 64% M-AAT with a 71% Z-AAT reduction and editing sustained at least three months, while KRRO-111 reached more than 90% SERPINA1 transcript editing and roughly 90% repaired AAT protein in vivo.
2. GalNAc hepatocyte delivery (GalNAc Delivery):
   • subcutaneous GalNAc conjugation targets the asialoglycoprotein receptor on hepatocytes, enabling liver-directed editing without lipid nanoparticles; AX-0810 showed an 8-fold NTCP target-engagement signal at 6 mg/kg with an approximately 8-week half-life, and WVE-006 is dosed 200 mg biweekly or 400 mg monthly with a dynamic AAT response (up to 20.6 µM total AAT during an acute-phase response).
3. Structure-guided arRNA design (Guide Design):
   • rational engineering of the ADAR-recruiting guide to expand the editable sequence space and remove bystander edits; HuidaGene’s LEAPER 3.0 (Cell, 2026) uses AlphaFold 3 to model the ADAR1/ADAR2–double-stranded-RNA interface and introduces inner and outer bulge structures that confine catalysis to the target adenosine.

07Value chains and production pipelines#

Industrial pipeline of an ADAR RNA-editing therapeutic (NDA / MAA, Directive 2001/83/EC)#

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Target & SNV selection │ ───> │ 2. arRNA/EON design       │
└───────────────────────────┘      └───────────────────────────┘
                                                  │
                                                  ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. Preclinical & clinical │ <─── │ 3. GalNAc conjugation &   │
└───────────────────────────┘      │    CMC                    │
               │                    └───────────────────────────┘
               ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Regulatory & approval  │ ───> │ 6. Launch & PV            │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Target and SNV selection

A pathogenic G-to-A transcript variant correctable by A-to-I editing is identified (for example the SERPINA1 Z-allele in AATD or the NTCP transporter in cholestatic liver disease), together with an ADAR-recruitment-compatible sequence context around the target adenosine.

Stage 2: arRNA/EON design

An ADAR-recruiting oligonucleotide — an AIMer (Wave), OPERA guide (Korro), Axiomer EON (ProQR) or arRNA (HuidaGene) — is engineered with stereopure chemistry and, in LEAPER 3.0, dual-bulge structures that position endogenous ADAR on the target adenosine while suppressing bystander editing.

Stage 3: GalNAc conjugation and CMC

The editing oligo is conjugated to a GalNAc ligand for ASGPR-mediated hepatocyte uptake and manufactured under stereopure oligonucleotide GMP, yielding a subcutaneously delivered drug substance that avoids lipid-nanoparticle formulation.

Stage 4: Preclinical and clinical

Editing-efficiency, PK and safety studies support IND filing and first-in-human trials; WVE-006 is in the RestorAATion-2 Phase 1b/2a trial (11.9 µM total AAT, 71% Z-AAT reduction, editing held at least three months), KRRO-110 is in the REWRITE Phase 1/2a study, and AX-0810 produced the first clinical target-engagement validation of an RNA-editing platform (8-fold bile-acid response at 6 mg/kg).

Stage 5: Regulatory and approval

A NDA (US) or MAA (EU) is filed as an oligonucleotide therapeutic under Directive 2001/83/EC, with orphan-drug designation and the accelerated-approval pathway available for rare indications such as AATD; FDA feedback on an accelerated-approval route for WVE-006 is expected mid-2026.

Stage 6: Launch and pharmacovigilance

Following approval, the reversible-edit drug launches under the oligonucleotide pharmacovigilance regime, with real-world monitoring of editing durability and re-dosing interval that the modality has not yet seen at scale, no RNA-editing drug being yet approved.